Conventional cancer treatment drugs such as 5-fluorouracil (5-FU), cisplatin and so on are associated with a problem of high expression rate of side effects. Therefore, the development of pharmaceutical agents that selectively act on the cancer cells has been ongoing, and imatinib (Glivec (trademark)), trastuzumab (Herceptin (trademark)) and so on have been placed on the market. All of these drugs target proteins that are specifically expressed in cancer cells. As to other cancer treatment drugs, the development of angiogenesis inhibitors that suppress angiogenesis necessary for the survival and metastasis of tumors has been currently undertaken. Angiogenesis inhibitors are pharmaceutical agents that show an anti-tumor effect by directly acting on the vascular endothelial cells around cancer cells, and indirectly acting on the cancer cells. Accordingly, reduction of side effects and different anti-tumor spectra are expected unlike the existing pharmaceutical agents.
As angiogenesis inhibitors, various pharmaceutical agents such as MMP (matrix metalloproteinase) inhibitors, anti-VEGF (vascular endothelial growth factor) antibodies, VEGF receptor tyrosine kinase inhibitors (VEGFR-TK inhibitors) and so on have been developed.
NF-κB is a transcription factor present in the cytoplasm, which is activated in response to the stimulation by IL-1, TNF-α and so on. As the gene products of NF-κB, MMP, IL-8 and so on involved in angiogenesis, and Cyclin D and so on involved in cell growth are known. In addition, NF-κB is known to express Bcl-2 and so on, thereby inducing apoptosis resistance of the cells. Furthermore, constitutive activation of NF-κB in cancer cells has been reported, and NF-κB is considered to constitute one of the factors supporting the properties of cancer cells, such as apoptosis resistance, metastasis via new blood vessels and so on.
It is considered that suppression of the activation of NF-κB having such properties and inhibition of the production of the gene product thereof will provide a promising effect of removing the apoptosis resistance of cancer cells and suppressing of angiogenesis, and that a novel angiogenesis inhibitor directly acting on cancer cells can be developed.
In the meantime, there are a number of indazole compounds synthesized to the present. However, the compounds described in WO03035005 (patent reference 1) are not known to have an anti-tumor activity, and the compounds described in WO03097610 (patent reference 2) and WO03028720 (patent reference 3) have an inhibitory action of protein kinase.
patent reference 1: WO03/035005
patent reference 2: WO03/097610
patent reference 3: WO03/028720